Our goal is to understand the molecular and biochemical processes that underlie birth defects. Although individually rare, genetic syndromes and malformations have a large impact on childhood morbidity and mortality. We are studying both a dysmorphic mouse and a human malformation syndrome. Our laboratory=s major effort has been in studying the Smith-Lemli-Opitz syndrome (SLOS). This is a human malformation syndrome characterized by a characteristic facial appearance, mental retardation, hypotonia, poor growth, decreased life span and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. Biochemically patients with SLOS have a defect in cholesterol biosynthesis. Specifically they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. Why these children have such a variety of malformations is not known. This past year, we cloned the gene encoding the 7-dehydrocholesterol reductase, and identified mutations in this gene in patients with Smith-Lemli-Opitz syndrome. We have also cloned the mouse gene encoding this enzyme and are producing a mouse model for this disorder. We plan to use the mouse model to further our understanding of how the malformations seen in this syndrome develop. We are also studying a genetically altered mouse that has forebrain malformations, anophthalmia and severe anemia. These malformations are due to inactivation of a gene known as Lhx2. We produced this mutation by gene targeting in embryonic stem cells. Lhx2 encodes a LIM homeobox protein that regulates the expression of other genes during development. We have also cloned and characterized a novel LIM homeobox gene that is closely related to Lhx2. This gene is known as Lhx9. In situ expression studies have shown that Lhx9 is expressed in Cajal-Retzius neurons of the developing brain and in the developing limb. In collaboration with the Laboratory of Mammalian Genes and Development, we have produced a mouse strain in which Lhx7 does not function. The developmental consequences of this mutation are being characterized. In addition, analysis of Lhx2/Lhx9 compound mutant mice is in progress.